Alzheimer's disease (AD) is characterized by the progressive loss of cognitive function and the accumulation of amyloid beta (Aβ) plaques in regions associated with learning and memory. While Aβ plaques were once thought to play a central role in the pathogenesis of AD, a growing body of evidence suggests that the Aβ-derived diffusible ligands (ADDLs) may be responsible for the disease-associated neuronal dysfunction and cognitive decline (Walsh and Selkoe, 2004, Protein Pept. Lett., 11: 213-228). ADDLs are small, soluble oligomers of Aβ that are abundant in AD, but not normal, brains (McLean et al., 1999, Ann. Neurol., 46: 860-866; Gong et al., 2003, Proc. Natl. Acad. Sci. USA, 100: 10417-10422). In vitro studies have shown that ADDLs, isolated from AD brain or synthetic preparations, bind to a subpopulation of cortical and hippocampal neurons (Gong et al., 2003; Klein et al., 2004, Neurobiol. Aging, 25: 569-580; Lacor et al., 2004, J. Neurosci., 24: 10191-10200; Shughrue et al., 2010, Neurobiol. Aging, 31: 189-202), while little or no binding was detected with fibrillar or monomer Aβ preparations (Lacor et al., 2004; Hepler et al., 2006, Biochemistry, 45: 15157-15167). Furthermore, ADDL binding to neurons can be attenuated with both polyclonal (Gong et al., 2003) and monoclonal antibodies (Lee et al., 2006, J. Biol. Chem., 281: 4292-4299; De Felice et al., 2007, Neurobiol. Aging 29: 1334-1347; Shughrue et al., 2010) generated against ADDLs.
In rodent models, the central administration of ADDLs induces deficits in rodent long term potentiation (LTP) and memory formation (Walsh et al., 2002, Nature, 416: 535-539; Cleary et al., 2004, Nat. Neurosci., 8: 79-84; Klyubin et al., 2005, Nat. Med., 11: 556-561). The effect of oligomers on LTP was attenuated when ADDLs were co-administered with an anti-Aβ antibody or administered to animals that were vaccinated with the Aβ peptide (Rowan et al, 2004, Exp. Gerontol., 39: 1661-1667). In a transgenic model of AD, such as transgenic mice that produce human amyloid precursor protein (hAPP), age-associated cognitive deficits have been observed with elevated ADDL levels (Westerman et al., 2002, J. Neurosci., 22: 1858-1867; Ashe, 2005, Biochem. Soc. Trans., 33: 591-594; Lee et al., 2006; Lesne et al., 2006, Nature, 440: 352-357). When hAPP mice were treated with an anti-ADDL antibody, a significant improvement in cognitive performance was observed without a concomitant decrease in Aβ plaque load (Lee et al., 2006). Together these findings suggest that ADDLs, and not Aβ plaques, are primarily responsible for cognitive impairment and that the use of anti-ADDL antibodies may prove efficacious in the treatment of AD. See also, US2006/0228349; U.S. Pat. No. 7,731,962, WO 2007/050359; US2007/0218499, WO 2006/014478; U.S. Pat. No. 7,700,099; US 2008/01758835, WO 2006/055178.
Accordingly, there is a need for ADDL-selective therapeutic antibodies for the prevention and treatment of AD. The present invention meets this need.